13-76991953-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000636183.2(CLN5):c.-146T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,562,804 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: -1.45

Genes affected

CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01180765).
• BP6: Variant 13-76991953-T-C is Benign according to our data. Variant chr13-76991953-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166884.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}. Variant chr13-76991953-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000987 (150/152042) while in subpopulation NFE AF= 0.00134 (91/67942). AF 95% confidence interval is 0.00112. There are 2 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000636183.2	c.-146T>C		5_prime_UTR_variant	1/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.000987 AC: 150 AN: 151924 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000799 AC: 128 AN: 160196 Hom.: 0 AF XY: 0.000754 AC XY: 67 AN XY: 88870

Gnomad AFR exome AF: 0.000121

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.00152 AC: 2150 AN: 1410762 Hom.: 2 Cov.: 32 AF XY: 0.00143 AC XY: 996 AN XY: 698630

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.000104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00237

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.000766

GnomAD4 genome AF: 0.000987 AC: 150 AN: 152042 Hom.: 2 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74340

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000953 Hom.: 0

Bravo AF: 0.000676

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000415 AC: 3

ExAC AF: 0.000417 AC: 47

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2022	Has not been previously published as pathogenic or benign to our knowledge; Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26990548) -

Neuronal ceroid lipofuscinosis 5 Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 03, 2018	The CLN5 c.2T>C (p.Met1?) variant is predicted to disrupt the initiator codon, and thus potentially may interfere with protein expression. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.002934 in the European (Finnish) population from the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact on protein expression and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Neuronal ceroid lipofuscinosis Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

CLN5-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2023

The CLN5 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.31% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-77566088-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Benign	-0.70
Cadd	Benign	3.6
Dann	Benign	0.40
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.00042	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N
ClinPred		0.034	T
GERP RS		-2.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201615354; hg19: chr13-77566088;